Annotation

November 2014

Guidelines regarding the use of pharmacogenomic tests in dosing for phenytoin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Excerpt from the 2014 phenytoin dosing guidelines:

"[A]t least a 25% reduction of the recommended starting maintenance dose may be considered for CYP2C9 intermediate metabolizers with subsequent maintenance doses adjusted based on therapeutic drug monitoring and response. For CYP2C9 poor metabolizers, consider at least a 50% reduction of starting maintenance dose with subsequent maintenance doses adjusted based on therapeutic drug monitoring or response."

"[R]egardless of the CYP2C9 genotype and individual's ancestry or age, if the HLA-B*15:02 test result is positive, the recommendation is to consider using an anticonvulsant other than carbamazepine and phenytoin unless the benefits of treating the underlying disease clearly outweigh the risks... Alternative medications such as oxcarbazepine, eslicarbazepine acetate, and lamotrigine have some evidence linking SJS/TEN with the HLA-B*15:02 allele and thus caution should be used in choosing alternatives to phenytoin."

b If the patient has previously used phenytoin for longer than 3 months without incidence of cutaneous adverse reactions, reinitiate phenytoin with caution. Adjust dose based on CYP2C9 genotype if known.

Annotated Labels

Summary

A strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLAB*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.

Annotation

Phenytoin sodium is an antiepileptic drug.

Excerpt from the phenytoin sodium (Dilantin) drug label:

There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference.

Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLAB*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.

Summary

The product monograph for phenytoin (DILANTIN) notes that individuals with the HLA-B*1502 allele have an increased risk of developing Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) when receiving the drug. It further notes that this allele is common in individuals of Asian ancestry, and HLA-B genotyping should be considered as a screening tool in these patients.

Annotation

Phenytoin (DILANTIN) is an anti-epileptic. Excerpts from the phenytoin (DILANTIN) product monograph:

In studies that included small samples of patients of Asian ancestry a strong association was found between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. The HLA-B*1502 allele is found almost exclusively in individuals with ancestry across broad areas of Asia. Results of these studies suggest that the presence of the HLA-B*1502 allele may be one of the risk factors for phenytoin-associated SJS/TEN in patients with Asian ancestry.

...physicians should consider HLA-B*1502 genotyping as a screening tool in these patients. Until further information is available, the use of phenytoin and other anti-epileptic drugs associated with SJS/TEN should also be avoided in patients who test positive for the HLA-B*1502 allele.

HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management.

Disclaimer:
The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed
literature available at the time they are written and are intended only to assist clinicians in decision-making
and to identify questions for further research. New evidence may have emerged since the time an annotation was
submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or
diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all
proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider
to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the
ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB
assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of
the PharmGKB clinical annotations, or for any errors or omissions.

?= Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the
"Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the
corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated
information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications
can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding
Variant Page.

PharmGKB Accession Id

PA450947

Type(s):

Drug

Description

An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.

Source: Drug Bank

Indication

For the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

Source: Drug Bank

Pharmacology

Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Phenytoin acts to dampen the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells. It lacks the sedation effects associated with phenobarbital. There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. Phenytoin is primarily metabolized by CYP2C9.

Source: Drug Bank

Food Interaction

Avoid alcohol.|Take with food to increase bioavailability and reduce irritation.|Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.

Route of Elimination

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2)
literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on
the "evidence" and "source" listed below.

Ticlopidine may decrease the metabolism and clearance of Phenytoin. Consider alternate therapy or monitor for adverse/toxic effects of Phenytoin if Ticlopidine is initiated, discontinued or dose changed.
(source: Drug Bank
)

Verapamil may increase the serum concentration of Phenytoin by decreasing its metabolism. Monitor for changes in the therapeutic/adverse effects of Phenytoin if Verapamil is initiated, discontinued or dose changed.
(source: Drug Bank
)

Warfarin may increase the serum concentration of phenytoin possibly by competing for CYP2C9 metabolism. Phenytoin may increase the anticoagulant effect of warfarin. Monitor phenytoin levels, prothrombin time, and therapeutic and adverse effects of both agents during concomitant therapy.
(source: Drug Bank
)